Several forms of hypetension in humans and animal models appear to result from hyperactivity of the sympathetic nervous system (SNS) attendant upon disturbances in SNS regulation by the central nervous system (CNS). Biogenic amine transmitters in the CNS, particularly norepinephrine (NE) and 5-hydroxytryptamine (5-HT) are involved in normal regulation of cardiovascular function and most likely in the development of hypertension. This proposal comprises a combined biochemical/physiological approach to establishing the relationship between disturbances in the CNS and production of hypertension or abnormal cardiovascular function in the rat. Central lesions of varying degrees of specificity for NE, 5-HT or dopamine will be produced by intracisternal administration of reserpine, 6-hydroxydopamine or 5,7-dihydroxytryptamine (the latter two with or without desmethylimipramine pretreatment which protects NE neurons) or by maternal reserpine administration, during critical periods in perinatal development; earlier work has shown that prior to the development of functional neuronal connections between CNS and SNS, animals are particularly susceptible to production of permanent alterations of CNS and SNS function. The specificity, extent and region for each type of CNS lesion will be evaluated biochemically by biogenic amine levels and synaptosomal uptake determinations. The effect of outgrowth and function of cardiac and adrenomedullary nerve supplies will be followed from birth through adulthood by measurements of presynaptic components (neurotransmitters, enzymes, synaptic vesicles) and by postsynaptic responses to nerve stimulation (cardioacceleration and ornithine decarboxylase induction in the heart, catecholamine release in the adrenal). In adulthood, extensive physiological studies will be undertaken to establish whether sympathetic tone or cardiovascular reflexes have been altered in the lesioned animals; these will involve recordings of sympathetic nerve activity, electrical stimulation of cardiac efferents, electrical stimulation of brain regions involved in cardiovascular function, and elicitation of SNS reflexes.